DESCRIPTION (provided by investigator): The proposed research explores the usefulness of a new high-resolution tissue molecular imaging method called Array Tomography (AT) to the understanding, diagnosis, prevention, and cure of Alzheimers Disease (AD). As part of this effort, a new set of array tomographic molecular labeling and image analysis methods, called Array Tomographic Single-Synapse Analysis (AT/SSA), will be developed for the purpose of quantifying and classifying individual synapses in tissues of mouse and human cerebral and hippocampal cortex. Loss of cortical synapses is widely believed to be the proximal cause of cognitive dysfunction in AD and many other neurodegenerative disorders, but quantitative information about such cortical synapse deficiencies has been limited, due to the technical limitations of available methodology. Moreover, cortical synapses are now recognized as being highly diverse, and again, relevant quantitative information is scarce. These shortcomings are consequential to human mental health because of strong evidence that different neurochemically defined synapse types exhibit differential pathologies in AD and therefore represent distinct therapeutic target discovery opportunities. AT/SAA is expected to provide new quantitative information about cortical synapse populations and their diversity that could fill critical gaps in our understanding of AD and lead to the development of novel diagnostic and therapeutic strategies. AT/SSA is based on the ability of array tomographic immunofluorescence imaging to resolve and quantify individual synaptic puncta in three-dimensional volumes of cortical neuropil, and the use of high-order antibody multiplexing to discriminate amongst various molecularly defined synapse types. This project will continuing efforts to make array tomography imaging methods faster, easier, more reliable and more informative and to develop high-throughput array tomographic classification tools for discrimination and quantification of synapse types. To establish a baseline quantifying normal cortical synapse populations, AT/SSA methods will be applied first to tissue specimens from wild-type mice and from autopsies and biopsies of humans unaffected by AD. The same methods will then be applied to specimens from transgenic, disease-model mice and from neurologically characterized AD patients. The information to be obtained is expected to provide new insights into the cellular and molecular basis of AD disease progression in human patients and to identify new ways that disease model mice may be used to help develop and test new drugs, vaccines, or other treatments aimed at the prevention and cure of AD. PUBLIC HEALTH RELEVANCE: The proposed research explores the potential usefulness of a new high-resolution molecular imaging technique called Array Tomography (AT) to the understanding, diagnosis, prevention, and cure of Alzheimers Disease (AD). A new set of AT-based methods will be developed and used to compare cortical synapses from the brains normal and AD-affected humans and from normal mice and mice genetically modified to mimic the human AD condition. The information to be obtained is expected to provide new insights into the cellular and molecular basis of AD disease progression in human patients and to identify new ways that disease model mice may be used to help develop and test new drugs, vaccines, or other treatments aimed at the prevention and cure of AD.